Borrelia burgdorferi

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Borrelia burgdorferi
B. burgdorferi at 400x magnification, dark field microscopy

B. burgdorferi at 400x magnification, dark field microscopy

Systematics
Department : Spirochaetae
Class : Spirochaetes
Order : Spirochaetales
Family : Spirochaetaceae
Genre : Borrelia ( Borrelia )
Type : Borrelia burgdorferi
Scientific name
Borrelia burgdorferi
Johnson et al. 1984, Baranton et al. 1992

Borrelia burgdorferi sensu lato ( Lat. Sensu lato [sl] = in a broad sense) is a group of closely related species of spirochetes - genus Borrelia . The main pathogens of Lyme borreliosis in humans and dogs are three types: Borrelia burgdorferi sensu stricto ( Latin [ss] = in the narrower sense), B. garinii and B. afzelii . The name goes back to Willy Burgdorfer , who isolated the bacterium in 1982. The pathogen's infection cycle includes two hosts : ticks of the genus Ixodes and small mammals . People infected by tick bites are a dead end for the bacterium. In other words , the chain of infection ends in humans.

features

Like other spirochetes, Borrelia burgdorferi is an actively mobile , helical , gram-negative bacterium with relatively few turns or turns. It is about 0.3 micrometers in diameter and can grow to 10 to 20 micrometers long. It uses wrapped flagella bundles for locomotion . The composition of the cell wall or the outer membrane changes depending on the phase of the infection cycle .

In in-vitro experiments, the bacterium can change its shape under certain conditions - for example nutrient deficiency or antibiotic administration - and survive as a spherical L-shape inside mammalian cells and possibly also in the extracellular matrix . L-form bacteria (discovered in 1935 at the Lister Institute , hence the name) have no or deficient cell walls and are therefore difficult to identify. The ability to divide and the influence on the pathogenesis of the Borrelia -L form in vivo is controversial, in cell cultures the ability to divide is retained.

Sensu lato and sensu stricto

As Borrelia burgdorferi sl a number of closely related Borrelia is called living in ticks and in mammals. In 2011, the group included the species B. afzelii , B. americana , B. andersonii , B. bavariensis , B. bissettii , Borrelia burgdorferi ss, B. californiensis , B. carolinensis , B. garinii , B. japonica in addition to some as yet unnamed Borrelia , B. kurtenbachii , as lusitaniae , B. sinica , as spielmanii , as tanukii , as Turdi , as valaisiana and B. yangtze .

At least three of the species lead to Lyme disease in humans: Borrelia garinii , B. afzelii and B. burgdorferi sensu stricto. The species cause slightly different immune reactions and clinical pictures, but without clear delimitation. An infection with B. burgdorferi ss is often associated with arthritis , while with B. garnii neurological symptoms and with B. afzelii skin changes are typical. Since the bacterial strain B31 of the species B. burgdorferi ss was the first to be sequenced , it is considered a reference .

Borrelia, which cause other diseases, such as B. recurrentis , the causative agent of relapsing fever, do not belong to the Borrelia burgdorferi sensu lato complex .

Distribution areas

Borrelia burgdorferi sl occur in Europe , Asia and the USA wherever both their tick host and their mammal host live.

In the USA, B. burgdorferi sensu stricto dominates. In Europe, B. afzelii and B. garinii most common, with both the prevalence of ticks considerable regional variation and the distribution of species. All known European species of B. burgdorferi sl have also been detected in Germany.

While B. burgdorferi in the US primarily by the hard ticks Ixodes scapularis ( deer tick , northeast and midwest) and Ixodes pacificus (West Coast) is transmitted to infect humans in Europe mainly through the bites of Commons wooden trestle ( I. ricinus ) and Asia through stings of the taiga tick ( Ixodes persulcatus ).

Infection cycle and transmission

Small rodents such as rats and mice as well as deer are the reservoir hosts of Borrelia burgdorferi ; they generally show no disease symptoms. Shield ticks serve as vectors ; that is, they transfer the bacteria to new reservoir hosts. Ticks and mammals are significantly different habitats in many ways (body temperature, pH , etc.) . In order to survive and multiply in both, B. burgdorferi adapts its gene expression and thus the spectrum of the synthesized proteins to the respective environment.

The tick larvae ingest the bacteria with their first blood meal on an infected rodent and, after they have developed into nymphs, transfer them to other hosts with their next meals. The bacteria visit the midgut of the nymphs where they attach themselves to their outer membrane with the help of the lipoprotein OspA. During the nymph's first meal, the blood and the rising temperature trigger changes in protein synthesis and chemotaxis : the Borrelia multiply, produce the lipoprotein OspC instead of OspA and migrate from the intestine to the salivary glands. From there they get to their next mammal host. After moulting again , the now adult ticks only suck the blood of larger mammals, which are not suitable reservoir hosts for B. burgdorferi and thus dead ends in their cycle.

Characteristic skin fluorescence after a tick bite

Both nymphs and adult ticks occasionally choose humans for their blood meals. Because the little nymphs are difficult to spot, their meal often lasts long enough to transmit spirochetes. They are therefore the main vector for infecting humans. In contrast to many other bacterial infections, human disease is not due to virulence factors such as toxins or specialized secretion systems , because B. burgdorferi is not evolutionarily adapted to human infestation. Instead, bacterial products that help the Borrelia to multiply and survive in their reservoir hosts, or the immune system's reactions to these substances, trigger Lyme disease.

genetics

The genome of the B31 strain of B. burgdorferi sensu stricto was the third microbial genome to be sequenced; the sequence was published in 1997. As is the case with many obligate parasites that depend on the metabolism of their hosts, the genome is relatively small. At the same time, it is highly complex and unusually structured, presumably in adaptation to the widely differing environmental conditions during the infection cycle: While most bacteria have a circular chromosome and also circular plasmids , the 910 kilobase pair chromosome is linear here, as are many of the 9 to 62 kilobase pairs large plasmids which together have a further 533,000 base pairs.

Each of the linear plasmids has a different structure. In addition to non-coding DNA and pseudogenes (i.e. genes inactivated by mutations ), all contain numerous copies of paralogue (i.e., homologous) genes created by duplication. The number and size of the plasmids as well as the arrangement of the genes on them differ within the complex B. burgdorferi sensu lato from species to species and from strain to strain. All of this suggests that the B. burgdorferi genome is in flux.

There is horizontal gene transfer both between strains and between species of B. burgdorferi sensu lato . The genes are presumably exchanged by transduction of the plasmid cp32 which is a prophage . Every B. burgdorferi strain examined so far contains numerous similar cp32 versions. Since cp32 carries numerous genes for surface lipoproteins such as OspC, which bind to proteins in the mammalian host, the accumulation of different cp32 variants presumably brings a survival advantage with it, since the Borrelia can colonize several mammalian species. The horizontal gene transfer allows beneficial mutations in the lipoprotein genes to spread rapidly in the Borrelia populations .

Many of the open reading frames of the genome, especially on the plasmids, show no homology to known genes from other bacteria; the function of their products is often unknown. Most of the known genes for basic metabolism are located on the chromosome, while most of the genes for lipoproteins in the outer bacterial membrane are located on plasmids. Almost 8% of all open reading frames encode lipoproteins; many of them are only expressed in certain phases of the infection cycle. The Borrelia in tick nymphs that have not yet sucked blood carry OspA in the outer cell membrane in order to adhere to the midgut. During the ticks' first blood meal, it is replaced by OspC, which is used to transmit to a mammal and to resist its innate immune response. During the permanent or persistent infection of the reservoir host, VlsE is expressed, with the help of which the Borrelia can hide from the immune system in the tissue (e.g. in the joints) of the host and absorb nutrients.

metabolism

B. burgdorferi has over the coevolution lost with its hosts the ability to self- amino acids , nucleotides , fatty acids and enzyme - cofactors to produce, and takes the necessary hydrocarbons , peptides and amino acids instead of the host on. The bacterium gains energy through glycolysis (breakdown of simple sugars ) and lactic acid fermentation (fermentation of sugars into lactic acid); It lacks the necessary genes for the citric acid cycle or oxidative phosphorylation . Because of its restricted metabolism, B. burgdorferi can only be cultivated in rich, not clearly defined nutrient media that are obtained from its hosts.

Like other Borrelia, B. burgdorferi manages without iron ; Instead, manganese is built into their metalloenzymes as a cofactor . This is the only way for the bacterium to survive in its hosts in an environment that is very poor in iron at times. A good 6% of the chromosomal genes encode products that contribute to the motility and chemotaxis of the bacteria and thus enable them to find the right niche in their hosts in every phase of the infection cycle.

Immune response and persistence

Both the innate defense (especially the complement system ) and the acquired defense (especially the humoral immune response , i.e. specific antibodies produced by plasma cells - less the cellular immune response ) participate in the immune reaction of mammals to a Borrelia infection . Both forms of defense curb the number of bacteria but cannot eradicate them. You can also become infected several times with B. burgdorferi .

This persistence of the infection is believed to be due to several mechanisms. On the one hand, the bacteria can persist in the connective tissue , where they are difficult for the immune system to reach between the extracellular collagen fibers . In experiments, they also invaded fibroblasts and survived inside, but such internalization is rare in vivo . On the other hand, the bacteria change their surface lipoproteins and thus their antigen structure in the course of immune evasion from generation to generation, so that they are poorly recognized by the specific antibodies. The antigen variation comes about through gene conversion in the vlsE locus, a non-reciprocal form of homologous recombination through which parts of the DNA sequence in this gene are repeatedly rearranged. The gene conversion is triggered by an as yet unknown signal in the reservoir host; it does not take place in Borrelia cultures or in ticks. The formation of long-lived antibody-producing B cells is weak and delayed.

In animal experiments, the original vlsE sequence is completely replaced by new variants within 28 days of the start of infection; recombinant B. burgdorferi thus have a strong selection advantage over the starting clone . In immunodeficient mice, the vslE sequences vary more slowly than in immunocompetent mice; the selection pressure is therefore mediated by VslE-specific antibodies, which bind more poorly to new variants.

Polymorphism

Numerous variants have been demonstrated of some genes and gene products that are important for infection and persistence (i.e. survival) in mammalian hosts. There are 16 main alleles of the ospC gene in the northeast of the USA alone . This polymorphism , which makes it easier for Borrelia to survive in different hosts and in different niches within a host, is obtained through balanced selection .

Two complementary mechanisms ensure that this diversity is preserved. Firstly, the immune response of the hosts gives the rarer variants a selective advantage, because an affected already by Borrelia host is by the reaction of his acquired defense against another Borrelia same ospC allele immune . A strain with a different ospC allele can still infect the host. On the other hand, the heterogeneous environment of the Borrelia in the various hosts and cycle phases ensures that none of the alleles has the greatest fitness under all conditions. Depending on the niche, i.e. on the type and tissue of the host, another OspC variant is advantageous. This polymorphism, like gene conversion, makes it difficult to develop an effective vaccine against B. burgdorferi .

literature

  • D Scott Samuels, Justin D Radolf: Borrelia: Molecular Biology, Host Interaction and Pathogenesis. Caister Academic Press, Norfolk UK 2010, ISBN 978-1-904455-58-5 , Chapter 6: Structure, Function and Biogenesis of the Borrelia Cell Envelope.

Individual evidence

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